Rates of Change in FEV₁ and DL_CO as Potential Indicators for mTOR Inhibitor Therapy in Pre-menopausal Lymphangioleiomyomatosis Patients

Abstract

The value of rates of change in FEV₁ and DL_CO to predict disease progression, and initiation of mTOR inhibitor therapy has not been evaluated.

In 84 pre-menopausal LAM patients, individual rates of change in FEV₁ and DL_CO and 95% confidence intervals (CI), were used to derive subsequent lowest values of FEV₁ and DL_CO that would prompt initiation of sirolimus therapy. These treatment criteria were compared with one based on FEV₁ or DL_CO ≤ 70 % predicted. In 12 patients undergoing sirolimus therapy both methods for determining the optimal point for initiation of therapy were evaluated.

Twenty-seven and 35 patients, respectively, who experienced rates of change in FEV₁ and DL_CO greater than expected, would have been excluded from therapy based on an FEV₁ or DL_CO > 70 % predicted. Twenty-five of the 84 patients were eventually treated but only when FEV₁ or DL_CO were ≤ 70 %. Applying such treatment criteria to 12 patients undergoing sirolimus therapy, would have delayed treatment for many years.

Pre-menopausal women in whom FEV₁ or DL_CO are declining at rates above the expected based on their individual rates of decline, should be considered for sirolimus therapy before the FEV₁ or DL_CO falls to ≤ 70 %.

Introduction

Lymphangioleiomyomatosis (LAM) is a rare disease that affects predominantly women and involves the lungs, causing cystic destruction, recurrent pneumothoraces and dyspnea, the thoraco-abdominal and pelvic lymphatics, leading to lymphatic masses, i. e., lymphangioleiomyomas, and chylous effusions, and the kidneys, where it may present as mixed mesenchymal tumors named angiomyolipomas (AML) [1]. LAM may occur sporadically and in subjects with an autosomal dominant neurocutaneous disorder, tuberous sclerosis complex (TSC) [1].

LAM cells contain mutations in the TSC genes TSC1 and TSC2, that encode the proteins hamartin and tuberin, respectively [2-4], which exist as a cytosolic complex. Tuberin is a GTPase-activating protein for Ras homolog enriched in brain (Rheb) [5]. Loss of hamartin or tuberin activity causes accumulation of active Rheb-GTP and stimulation of its effector, mechanistic target of rapamycin complex 1 (mTORC1), which results in increased cell size and proliferation [5]. This finding lead to the concept that mTOR inhibitors, such as sirolimus, could be used to treat patients with LAM, and was followed by the Multicenter International Lymphangioleiomyomatosis Efficacy and Safety of Sirolimus (MILES) double-blind controlled study of sirolimus in patients with LAM [6].

The MILES trial showed that sirolimus stabilizes lung function in patients with FEV₁ ≤70 % predicted [6]. Isolated reduction in DL_CO ≤70 % was not a criteria for enrollment. Accordingly, the MILES trial criteria for initiation of mTOR inhibitor therapy excluded patients with FEV₁ >70 % who, by the time their FEV₁ declined to 70 % predicted or less, might have lost one third or more of their lung function.

Although there is general agreement that LAM patients with chylous effusions and lymphangioleiomyomas, and angiomyolipomas benefit from m-TOR inhibitor therapy [1], no criteria based on FEV₁ or DL_CO and their rates of decline , except those derived from the MILES trial, have been proposed to identify LAM patients at risk for disease progression who may benefit from earlier initiation of mTOR inhibitor therapy. The problem with identifying such patients at an earlier date is that rates of decline of FEV₁ and DL_CO are variable [7-9]. Johnson and Tattersfield [8] reported a mean (±SD) rate of FEV₁ decline of 118±142 ml per year in 43 patients and a rate of DL_CO decline of 0.905±1.54 ml/min/mmHg in 33 patients. They noted that the greater the number of tests employed in deriving the slopes of FEV₁ and DL_CO per year, the less the variation between measurements. Another group [9] reported mean (SEM) rates of FEV₁ decline of 75±9 ml (1.7±0.4 % predicted) and a reduction in DL_CO of 0.69±0.07 ml/min/mmHg (2.4±0.4 % predicted) per year. This study however comprised post-menopausal patients, and patients with LAM-TSC, who may have had milder lung disease [9]. Other studies, reported higher rates of decline in FEV₁ in patients with reduced DL_CO [10], patients with FEV₁ ≤ 70 % predicted [11], patients presenting with dyspnea instead of pneumothorax [12], and patients with a positive response to bronchodilators [13], suggesting that such patients may warrant earlier sirolimus therapy. Given these data, we questioned whether waiting to start mTOR inhibitor therapy until patients have experienced reductions in FEV₁ or DL_CO to ≤ 70 % predicted was a justifiable criteria for therapy.

Apart from the European Respiratory Society and American Thoracic Society/Japanese Respiratory Society consensus statements suggesting that sirolimus may be considered for patients with rapid decline in lung function [14,15], no guidelines for initiation of mTOR inhibitor therapy or enrollment in clinical trials based on accelerated loss of function have been established. Such a determination depends on whether a decline in FEV₁ or DL_CO corresponds to true progression of disease or is a random variation without clinical significance; several other factors such as the reproducibility of the test and the quality of the testing need to be considered.

Although LAM may have varying clinical courses and different factors may affect rates of disease progression, the aim of our study was to assess the value of past rates of functional decline in predicting future FEV₁ or DL_CO values to provide a method for potentially anticipating therapy with sirolimus prior to greater losses in lung function. We focused our research on pre-menopausal patients only and defined a rapid decline in FEV₁ or DL_CO as one that is greater than the greater 95 % confidence interval for the individual rates of decline based on four tests performed within 18 months. Accordingly, the aims of our study were to determine whether measurement of four or more FEV₁ or DL_CO performed over 18 months could predict future declines in lung function, which might prompt earlier initiation of mTOR inhibitor therapy. The rationale to also evaluate a treatment criteria based on rates of decline of DL_CO and a DL_CO ≤ 70 % predicted was prompted by those patients who have FEV₁ above 70 % predicted , and experience persistent decline in DL_CO . Inasmuch as such patients were not the subject of the MILES trial, we thought that excluding LAM patients with reduced DL_CO from this analysis appeared to be inappropriate.

Material and Methods

Patient populations.

From a cohort of 173 patients participating in a LAM natural history and pathogenesis protocol (NHLBI Protocol 95-H-0186), that was approved by the National Heart, Lung, and Blood Institute Institutional Review Board, we identified 84 pre-menopausal patients seen within a span of five years who are the subject of this study. The demographic features of the 84 patients are shown on Table 1. Patients were diagnosed with LAM based on clinical, radiographic, and histopathologic criteria (Table 1) [14,15]. Eighteen patients had TSC-LAM and the remaining 66 had sporadic LAM. Twenty-five patients were eventually treated with sirolimus but all data presented here were obtained before therapy.

Table 1.

Demographic features of 84 pre-menopausal lymphangioleiomyomatosis patients

Number of patients	84
Age of LAM diagnosis	34.7±7.1
Age of first symptoms	32.0±7.2
History of pneumothorax	48 (57 %)
History of TSC	18 (21 %)
History of chylothorax	19 (22 %)
History of lymphangioleiomyomas	26 (31 %)
History of angiomyolipoma	49 (58 %)
History of anti-estrogen therapy	29 (34 %)
History of pneumonia	7 (8 %)
Initial presentation
Dyspnea	25 (30 %)
Pneumothorax	33 (39 %)
Hemoptysis	7 (8 %)
Abdominal pain	5 (6 %)
Cough	4 (5 %)
Chest pain	3 (3 %)
No symptoms	7 (8 %)
Mode of diagnosis
Lung biopsy	43 (51 %)
Abdominal mass biopsy	6 (7 %)
Characteristic CT and TSC	10 (12 %)
Characteristic CT and lymphangioleiomyoma	8 (10 %)
Characteristic CT and angiomyolipoma	7 (8 %)
Characteristic CT and chylous effusion	1 (1 %)
Characteristic CT scan and elevated serum VEGF-D levels	2 (2 %)

To characterize the pattern of lung function decline in patients who eventually were begun on mTOR inhibitor therapy, we also examined lung function data from a cohort of 118 LAM patients undergoing therapy with mTOR inhibitors. Among those patients we identified 12 without evidence of lymphatic disease, who were started on sirolimus therapy because of an FEV₁ and/or DL_CO≤ 70 % predicted and for whom lung function studies comprising many years of observation prior to therapy, made possible to assess pre-therapy patterns of lung function decline. The aim of this component of our research was to determine how many years and what rates of decline were experienced prior to initiation of treatment based either on a FEV₁ ≤ 70 % predicted or a DL_CO ≤ 70 % predicted. This group of patients were tested every six to every twelve months. Clinical, laboratory tests, chest X rays, and pulmonary function were obtained at each visit. Exercise tests and imaging studies were obtained respectively, yearly and every two years. All FEV₁ values reported in the manuscript refer to pre-bronchodilator data.

Pulmonary function testing.

Lung volumes and flow rates were measured using a Master Screen PFT, Erich Jaeger; (Wuerzburg, Germany) system according to American Thoracic Society/European Respiratory Society standards [16-18].

Study design.

We estimated individual yearly rates of change of FEV₁ and DL_CO in 84 subjects seen within a time-span of five years, who were tested at least five times, where the most recent test was within eighteen months of the previous one. The most recent visit was excluded from the derivation of the rates of change (slope) of FEV₁ and DL_CO. The remaining visits were used to derive the slopes and 95 % confidence interval for each subject (9). Then, for each subject, we determined the expected lower values of FEV₁ and DL_CO using their individual rates of change, the higher limit of the 95% CI, the last measurement used in the derivation of slopes, and the time elapsed from this visit until the next measurement of FEV₁ and DL_CO.

Although the reproducibility of DL_CO measurements is considered to be less than that of FEV₁, there are LAM patients in whom FEV₁ is well preserved and DL_CO is reduced and declines progressively. We suggest that in these patients, a decline in DL_CO, indicates progression of lung disease that may be confirmed by exercise testing that may uncover worsening exercise-induced hypoxemia, and by quantitative computed tomography grading of cystic lung disease severity. We believe that patients with a percent-predicted FEV₁ above 70 % and a declining DL_CO should be considered for sirolimus therapy

We hypothesized that if the last actual % predicted FEV₁ or DL_CO measured were lower than the expected lower limit calculated from the individual rates of decline of % predicted FEV₁ or % predicted DL_CO, treatment with mTOR inhibitors would be considered. That is, the calculated expected lower limit of FEV₁ or DL_CO was compared to the last actual measurement not used in the derivation of slopes. If these values were lower than the expected, patients were considered to have rapid decline in function. These expected lower limits of FEV₁ or DL_CO were taken to be a threshold below which treatment would be considered.

Three algorithms were used to assess whether treatment would be considered or not: 1) if the last actual % predicted FEV₁ was lower than its expected lower limit calculated above, treatment would be considered. 2) if the last actual % predicted DL_CO was lower than its expected lower limit calculated above, treatment would also be considered. The criteria for treatment based on the above analytic methods were compared to 3) conventional treatment criteria based on % predicted FEV₁ or DL_CO ≤70%.

Results

Demographics.

The mean age of the 84 pre-menopausal patients was 38.5±6.6 (19-46) years. Age of diagnosis and age of first LAM-related symptoms were respectively, 34.7±7.1 (18.7-45.5) and 32.0±7.2 (16.7-44.2) years. Demographic features of these patients are shown on Table 1. The mean age of the group of 12 patients who were eventually started on sirolimus was 37.8±9.4 (range, 24-53) years at the time of the first visit, and 51.4±9.8 (range, 35-68) years at the time of initiation of mTOR inhibitor therapy.

Indications for mTOR inhibitor therapy based on individual rates of change of FEV₁ and DL_CO and its 95 % confidence intervals.

The 84 pre-menopausal patients underwent a total of 526 tests. All pulmonary function data were collected over a period of five years [8]. The mean (SEM) yearly rate of change of FEV₁ was −72±13 ml (95% confidence interval −98, −46 ml) or −1.93±0.46 percent predicted (95% confidence interval −2.84, −1.03 % predicted). The mean (SEM) yearly rate of change in DL_CO was −0.49±0.11 ml/min/mmHg (95% confidence interval −0.70, −0.27 ml/min/mmHg) or −1.97± 0.51 percent predicted (95% confidence interval- 2.98, −1.03 % predicted).

Among the 84 patients (Table 1) we identified 27 (32.1 %) with decline in FEV₁ and 35 (41.7 %) with decline in DL_CO greater than expected. The average rates of change in FEV₁ and DL_CO in 35 pre-menopausal patients with FEV₁ ≤ 70% and 39 patients with DL_CO ≤70 % predicted were respectively, −112±19 ml (95 % confidence interval −151, −73 ml) or −3.59 ±0.67 % predicted (95% confidence interval −4.91, −2.27 % predicted), and −0.63±0.14 ml/l/mmHg (confidence interval −0.91, −0.3 ml/min/mmHg) or −2.75±0.70 % predicted (95% confidence interval −4.12, −1.38 % predicted). Of these, 15 and 24, respectively, also met the FEV₁≤70 % and the DL_CO ≤70 % criteria for mTOR inhibitor therapy. However,12 patients with decline in FEV₁ greater than expected, and 11 with declines in DL_CO greater than expected would not have been treated if the criteria used for treatment was a % predicted FEV₁ or a % predicted DL_CO ≤70 %.

The expected median interquartile rate (IQR) time to get to a % predicted FEV₁ ≤ 70 % in subjects with FEV₁ decline greater than expected was 7.4 years (4.0, 13.4 years). For the DL_CO the expected median (IQR) time to get to a % predicted DL_CO ≤70 % in subjects with greater than expected decline was 13.6 years (2.3, 24.4 years). We used median instead of mean values because the distribution is skewed.

We also focused on how long it would take in patients with FEV₁ or DL_CO > 70 % predicted for these functional parameters to be reduced to ≤ 70 % predicted. We identified 16 patients with FEV₁ > 70 % predicted who were followed for 8.3±4.5 years. FEV₁ was reduced from 87±13 % predicted to 68±2 % predicted (p<0.001) at an annual rate of 88±11 ml/year or 2.4 ±0.3 % predicted per year (Table 1S). In 20 patients with DL_CO > 70 % predicted followed for 7.4±4.8 years, DL_CO declined from 83±13 % predicted to 67 ±3 % predicted at an annual rate of 0.74±0.09 ml/min/mmHg, or 2.9±0.4 % predicted per year . Off these patients only eight and six, respectively, were eventually treated with sirolimus but not before FEV₁ or DL_CO had fallen to ≤ 70 % predicted.

Indications for mTOR inhibitor therapy based on individual rates of change in FEV₁ or DL_CO and its 95 % confidence intervals in patients with FEV₁ or DL_CO > 70 % predicted.

The average rates of change in FEV₁ and DL_CO in pre-menopausal patients with FEV₁ or DL_CO > 70 % predicted were respectively, −63±25 (95 % confidence interval −39, 164 ml) or −0.75 ±0.58 % predicted (95% confidence interval −1.94, 0.44 % predicted) and −0.20±0.11 ml/min/mmHg (95 % confidence interval −0.66, 0.26 mlin/mmHg) or −1.29±0.74 % predicted (95% confidence interval −2.75, 0.18 % predicted). Of this sub-group of patients (Table 3), 12 (24.5 %) had lower than the expected FEV₁, and 11 (24.4 %) had lower than the expected DL_CO (Table 3). Two of the 23 patients had greater than expected rates of decline in FEV₁ and DL_CO. The remaining patients had a decline in at least one of the two criteria.

Table 3.

Analysis of potential treatment of LAM patients based on a method derived from rates of decline in pre-menopausal patients with FEV₁ or DL_CO > 70 % predicted ^*

	Treated Based on Analytical Method
	Yes	No	Total
FEV1> 70 %	12 (24.5)	37 (75.5)	49 (100.0)
DLCO> 70 %	11 (24.4)	34 (75.6)	45 (100.0)

^*Columns show the numbers of patients to be treated with mTOR inhibitors when the observed FEV₁ and DL_CO were lower than the expected values derived from rates of decline in FEV₁ and DL_CO. Percentages of patients are shown within parenthesis.

Time course and rates of change in FEV₁ and DL_CO preceding therapy in 12 LAM patients treated with mTOR inhibitors.

Initial mean FEV₁ and DL_CO were respectively, 2.8±0.5 liters (97±10 % predicted) and 20.6±3.9 ml/min/mmHg (89.1±11.5 % predicted) (Table 4). We measured the rates of change of FEV₁ and DL_CO using four tests and compared FEV₁ and DL_CO values from the fourth test with values from tests performed 9.8±4.1 months later. We found that during this period of time FEV₁ and DL_CO changed by −3.3 and −5.3 % predicted respectively and % predicted FEV₁ and DL_CO values were significantly lower than those observed on the last test utilized to estimate the rates of change (Table 4). By the time the patients were began on therapy, FEV₁ and DL_CO had declined even further, to 1.7±0.4 liters (68.4±19.2 % predicted) and 12.4 ± 2.8 ml/min/mmHg (60.8±11.8 % predicted) respectively.

Table 4.

Lung function tests on first visit, time of estimation of rates of FEV₁ and DL_CO declines, the next test, and before and after sirolimus therapy in 12 patients with LAM.

	First test	Last slope test	Next test	Pre-sirolimus	Post-sirolimus
Age (years)	35.6±9.4	41.2±9.3	42.0±9.2	49.4±9.6	53.3±10.3
TLC (liters)	5.1±0.5	5.2±0.7	5.2±0.6	5.2±0.8	4.6±0.8
TLC (% predicted)	100.6±9.1	101.5±11.2	100.8±10.3	105.2±17.4	93.0±12.3
FVC (liters)	3.6±0.6	3.6±0.4	3.5±0.5	3.1±0.7	3.0±0.6
FVC (% predicted)	100.8±13.7	104±12.3	101.4±13.8	89.3±36	94±15.1
FEV1 (liters)	2.8±0.44	2.45±0.23	2.28±0.28	1.72±0.48	1.62±0.4
FEV1 (% predicted)	97±10.1	90.2±11.1	85±13	68.4±19.2	67.6±17.9
DLCO (ml/min/mmHg/year)	20.6±3.9	16.45±2.3	15.1±1.9	12.4±2.8	11.2±3.4
DLCO (% predicted)	89.1±11.5	77.6±7.9	71.6±7	60.8±11.8	56.5±14.7
Change in FEV1 (ml/year)		-		−105±17	−40±24
Change in FEV1 (% /year)		−3.7±1.3	−3.3	−3.0±0.5	−1±0.8
Change in DLCO (ml/min/mmHg)		-		−0.66±0.06	−0.05±0.14 *
Change in DLCO (% /year)		−2.6±1.5	−5.3	−2.6±0.3	0.02±0.6 *
Time since first test (years)	-	5.9±2.8	6.7±2.8	14.1±4.6	18.0±4.8

^*p=0.001

Discussion

This is the first study where an analysis of rates of decline in FEV₁, and DL_CO, predicts greater loss of function before patients cross the 70 % predicted FEV₁ threshold, that based on the MILES study became an accepted standard for initiation of sirolimus therapy. In the current study we show that in 84 pre-menopausal LAM patients, using individual rates of functional decline in FEV₁ or DL_CO, and 95 % confidence intervals, an analytical method using estimated expected % predicted FEV₁ or DL_CO based on past rates of FEV₁ or DL_CO declines identifies patients with faster loss of lung function who had not yet crossed a therapeutic threshold of % predicted FEV₁ or DL_CO ≤ 70 % predicted. These patients are at risk of experiencing a progressive loss of function before being considered for therapy.

Currently, mTOR inhibitor therapy may be recommended for subjects with lymphatic disease, and size or complications of angiomyolipomas, and those patients, who based on the MILES study enrollment criteria, have % predicted FEV₁≤ 70 %. Two consensus statements have suggested also that subjects with rapid disease progression should be considered for therapy, but rapid progression of disease was not defined [14,15].

In our study we found that 23 of 49 pre-menopausal patients with FEV₁ or DL_CO >70 % predicted, also experienced changes in FEV₁ or DL_CO greater than the higher 95 % confidence interval. These data suggest that some pre-menopausal LAM patients with % predicted FEV₁ or DL_CO > 70 %, may experience declines in lung function that in a given time will cause reductions in FEV₁ or DL_CO to ≤ 70 % predicted. Our data suggest that such patients should undergo frequent lung function testing to calculate rates of decline of FEV₁ and DL_CO over time. Subsequent testing will determine whether FEV₁ or DL_CO values are lower than the expected values derived from the lower limit of the 95% confidence interval.

It should be noted however, that it has not yet been established whether a patient whose lung function is falling but still has an FEV₁ or DL_CO above 70 % predicted should receive mTOR inhibitor therapy. Our data suggest that at a minimum, these patients are at additional risk for progression of lung disease and warrant close follow-up with frequent monitoring of disease by lung function testing and estimation of rates of FEV₁ and DL_CO decline. In the case of DL_CO, disease progression may also be confirmed by other means such as new onset of exercise-induced hypoxemia, or quantitative grading of lung disease by computed tomography, which if confirmed, may further ascertain the need for initiation of therapy. The alternative to this approach, waiting to initiate of mTOR inhibitor therapy until either FEV₁ or DL_CO have fallen to or under 70 % predicted, may result in greater loss in lung function. This was confirmed by data from 12 patients who eventually were begun on sirolimus therapy, because of reductions in FEV₁ and/or DL_CO from values at or above 80 % predicted to values ≤ 70 % predicted (Table 4). Indeed, after measuring rates of decline in lung function employing four tests, we found that a fifth test performed within a year showed further losses in lung function. Treatment with mTOR inhibitors should have been started at that point instead of much later, when patients had already lost more than 20 % of the FEV₁ and 15 % of the DL_CO (Table 4). We suggest that a case can be made for initiation of therapy for those patients in whom tests done after estimating the rate of decline in function demonstrate persistent large declines in FEV₁ or DL_CO. Such decision must be balanced against the risks of drug toxicity. Perhaps in patients who have not yet reached the 70% predicted FEV₁ or DL_CO threshold, low dose sirolimus therapy could be considered [19].

We compared using the individual 95 % confidence of rates of change in FEV₁ or DL_CO, versus the confidence interval for the entire group mean rates of decline in FEV₁ or DL_CO. A lesser number of patients who would be potential candidates for mTOR inhibitor therapy was identified when individual rates of decline were employed. Indeed, the analysis based on group rates performed better than one based on individual rates and 95 % confidence limits. However, similar data from relatively large LAM patient population are not available to practicing physicians. Therefore, we suggest using individual rates and a minimum of four tests within a period of 18 months to estimate the changes in FEV₁ and DL_CO. If subsequent testing yields FEV₁ or DL_CO values lower than the expected lower limit, and in absence of an obvious cause for this change such as a recent pneumothorax, pleurodesis or intercurrent respiratory infection, initiation of mTOR inhibitor therapy should strongly be considered.

In our experience, the reproducibility of FEV₁ measurements in LAM patients is generally good, but an occasional patient may experience differences that may reach 7 to 8 % between two measurements (online supplemental Figure 1S). In the case of DL_CO the problem is more complex, because of the greater intra-individual variability of this test [17]. In this case, exercise testing and imaging studies, may assist in determining whether a measured reduction in DL_CO parallels new onset of exercise-induced hypoxemia or increase in lung cysts.

A major concern with this approach is the timing of initiation of therapy in patients in whom lung function is declining at a steady, yet slow, rate. Let us take a patient in whom FEV₁ or DL_CO declines every year but at a slow rate of 1-2 % per year. Should treatment be started when their values reach under 80 % predicted? It remains also to be defined if earlier initiation of mTOR inhibitors, including in those with normal FEV₁ and DL_CO or FEV₁ or DL_CO above 100 % predicted, would be beneficial for patients with LAM. We suggest however, that evaluation of the rate of change in FEV₁ and DL_CO may have a special importance in those patients in whom values of FEV₁ or DL_CO are above 100% of predicted. In this population, to wait until FEV₁ and DL_CO reach 70% of predicted to initiate the use of sirolimus would be more deleterious because it results into a 30 % loss of lung function. Measurement of cyst scores by computed tomography may help defining progression of disease [20]. At present, definite answers to these questions can not be provided.

Based on our data, we recommend that pre-menopausal LAM patients in whom lung function is declining steadily at rates well above the expected based on their estimated rates of decline, should be followed closely and be strongly considered for mTOR inhibitor therapy before the FEV₁ or DL_CO falls to ≤ 70 % predicted.

Figure 1.

Venn diagram representing the FEV₁ and DL_CO profile of 84 LAM pre-menopausal patients. Of the 84 patients, 49 and 45 respectively, had FEV₁ or DL_CO above 70 % predicted. Thirty-five patients had an FEV₁ ≤ 70 % predicted and 39 had a DL_CO ≤ 70 % predicted. Twenty-nine patients had both FEV₁ and DL_CO ≤ 70 % predicted. Twelve of the 49 patients with FEV₁> 70 % predicted and 11 of the 45 patients with DL_CO> 70 % predicted had greater than expected declines in in FEV₁ and DL_CO, respectively.

Table 2.

Comparator analysis of treatment of 84 pre-menopausal LAM patients based on lung function criteria versus an analytical method derived from individual rates of functional decline and confidence intervals ^*

Percent predicted FEV1 N (%)		Treated Based on Analytical Method
		Yes	No	Total
FEV1 ≤70 %	Yes	15 (17.9)	20 (23.8)	35 (41.7)
	No	12 (14.3)	37 (44.0)	49 (58.3)
	Total	27 (32.1)	57 (67.9)	84 (100)
Percent predicted DLCO N (%)		Yes	No	Total
DLCO ≤70 %	Yes	24 (28.6)	15 (17.9)	39 (46.4)
	No	11 (13.1)	34 (40.5)	45 (53.6)
	Total	35 (41.7)	49 (58.3)	84 (100)

^*Rows show the number of patients who would be treated with mTOR inhibitors if FEV₁≤70 % predicted or DL_CO ≤70 % predicted. Columns show the number of patients to be treated with mTOR inhibitors when the observed FEV₁ or DL_CO was lower than the expected values derived from rates of decline in FEV₁ and DL_CO. Percentages of patients are shown within parenthesis.

Take home message:

Past rates of FEV₁ or DL_CO decline are indicators of future lung function loss and initiation of sirolimus therapy.